Many tumor-bearing animals develop antibodies to unique antigens associated with the oncogenic virus causing the tumor. These antigens, called "neoantigens," have been found in tumors caused by papovaviruses, adenoviruses, and herpes viruses. Hepatitis B virus, a hepadnavirus with suspected oncogenic potential, cannot be transmitted to non-primates but patients with HBV-associated hepatoma might be expected to have antibody to a HBV-associated neoantigen if one exists. Using a hepatoma cell line that contains integrated HBV DNA, we sought immunofluorescent antibody in sera of hepatoma patients. Approximately seven percent of sera from HBsAg-positive hepatoma patients contained an antibody that reacted with a nuclear antigen in the hepatoma cell line. This antigen was found in another hepatoma cell line that also contained integrated HBV genome but not in two other hepatoma cell lines lacking HBV genome. The antigen ("hepatitis B virus-associated nuclear antigen": HBNA) is being further characterized to determine if it is the product of a transforming gene. A different nuclear antigen was found in a human hepatoma cell line that did not contain HBV DNA. It was identified with serum from a patient with HBsAG negative hepatocellular carcinoma. The new antigen has characteristics similar to those of HBNA.